73963-72-1 Usage
Description
Cilostazol is a potent cyclic nucleotide phosphodiesterase inhibitor, primarily used as an antiplatelet agent. It is a platelet aggregation inhibitor with cerebral vasodilating activity, indicated for use in stroke and myocardial infarction. Cilostazol is a colorless, needle-like crystal that is easily soluble in acetic acid, chloroform, N-methyl-2-pyrrolidone, or dimethyl sulfoxide and almost insoluble in ether, water, 0.1mol/L hydrochloric acid, or 0.1mol/L sodium hydroxide. It is known by the brand names Pletal (Otsuka) and Reta.
Uses
Used in Pharmaceutical Industry:
Cilostazol is used as an antiplatelet agent for inhibiting platelet aggregation caused by various inducers and aggregates, preventing secondary aggregation. It has significant antithrombotic effects on brain circulation and peripheral circulatory disturbances caused by collagen, ADP, arachidonic acid, and sodium laurate. It is also used for treating ischemic diseases such as chronic arterial occlusive ulcer, pain, and coldness.
Used in Cardiovascular Applications:
Cilostazol is used as a phosphodiesterase III inhibitor for its cardiotonic properties, helping in the treatment of stroke and myocardial infarction. It significantly inhibits ADP-, collagen-, and epinephrine-induced platelet aggregation in patients with cerebral thrombosis, transient ischemia, and cerebral arteriosclerosis.
Used in Antithrombotic Treatments:
Cilostazol is used as an antithrombotic agent for its vasodilatory effects, improving blood flow in the brain and peripheral circulation, and reducing the risk of thrombus formation.
Used in Inhibiting Phosphodiesterase III:
Cilostazol is used as an inhibitor of phosphodiesterase III, which helps in regulating the levels of cyclic nucleotides in the body, contributing to its antiplatelet and vasodilatory effects.
Used in Affecting Lipid Levels:
Cilostazol is used for its effects on lipid levels in vivo, potentially contributing to the management of cardiovascular health.
Pharmacological effects
Cilostazol is commonly used clinically anti-platelet and anti-clotting drugs. It belongs to a phosphodiesterase inhibitor and can inhibit the activity of phosphodiesterase of platelet and smooth muscle cells, leading to increase of the cAMP concentration in platelets and vascular smooth muscle. It can significantly inhibit the platelet aggregation induced by various kinds of aggregation inducers, and can cause the dissociation of the aggregates. Its major metabolite, epoxide has a three to four fold activity of the prototype drug. It has significant antithrombotic effect on the brain circulation and peripheral circulatory disturbance caused by collagen, ADP, arachidonic acid and sodium laurate. Artery injection of this product can increase the blood flow rate with the strongest effect on the peripheral blood vessels but the weakest effect on the cerebral blood vessels.
This product is rapidly absorbed in the intestine after oral administration with the Tmax being 3h, PPB being about 95%. Consecutive administration of four days by twice per day caused no increase in the plasma concentration accumulation. It has good tissue distribution with especially high level in the stomach, liver and kidney. At 72h after administration, 42.75% of the administered drug is excreted via urine and 61.7% is subject to fecal excretion. After 48 hour of administration, bile excretion rate is 31.7%. T1/2α is 2.2h and T1/2β is 18h.
Clinical application
It can be used to alleviate the ischemic symptom such as ulcers, limb pain, cold sensation and intermittent claudication caused by chronic arterial occlusive disease. It can also be applied to the adjuvant treatment of atherosclerosis, arteritis, thromboangiitis obliterans, diabetes-induced ischemia of extremity and takayasu arteritis. Cilostazol also be used as a complementary therapy after surgical treatment to help alleviate the symptoms, improve the circulation and inhibiting thrombosis in transplanted blood vessel.
Side effects
There may be occasionally rash, hives, itching, palpitations, pulse frequency, low blood pressure, fever, dizziness, dizziness, vertigo, insomnia or drowsiness, swelling, pain, fatigue, weakness, stomach discomfort, nausea, vomiting, loss of appetite, diarrhea, upper abdominal pain, abdominal fullness, increased level of GOT (serum alanine aminotransferase), ALP (serum alkaline phosphatase), LDH (serum lactate dehydrogenase), BUN (blood urea nitrogen), creatinine and uric acid, gastrointestinal bleeding, epistaxis, subcutaneous bleeding, retinal hemorrhage, hematuria, bleeding tendencies and thrombocytopenia.
The above information is edited by the lookchem of Dai Xiongfeng.
Precautions
Patients of hemophilia, capillary fragility syndrome, upper gastrointestinal bleeding and urinary tract bleeding as well as vitreous hemorrhage should be disabled. Women of pregnancy or possible pregnancy should be disabled.
This product is should be taken cautious when being applied to patients in the use of anticoagulants (warfarin) or antiplatelet drugs (aspirin, Ticlid) patients. When using cilostazol, the patients should be subject to blood coagulation performance test.
Women in menstrual period, patients of bleeding tendency or with severe hepatic and renal dysfunction as well as elderly should administer with caution; breast-feeding women should avoid breast-feeding.
Production method
Take 5-chloro-N-cyclohexyl pentanamide as the raw material. Under ice-cooling, to 15 mL of benzene solution containing 1.75g ??5-chloro-N-cyclohexyl-pentyl amide solution, slowly add 1.9 g of phosphorus pentachloride and stir at room temperature for 1h. At room temperature and stirring, add 1.4mol/L HN3 to 1 mL of the benzene solution. After stirring overnight, continue the reflux for 2h. The solvent was distilled off under reduced pressure with the residue being poured into ice water and subject to chloroform extraction. The extract was successively washed with water, dilute sodium bicarbonate solution and water, further dried by anhydrous sodium sulfate. After the chloroform was distilled off, the residue was subject to isopropanol-water recrystallization to obtain 1.7 g of 5-(4-chlorobutyl)-l-cyclohexyl-tetrazole, being as colorless needle-like crystals with the yield being 87% and the m.p. being 48-49 ℃.
Dissolve 3.2 g 6-hydroxy-3, 4-dihydrogen-2(1H)-quinolinone and 1.4 g of potassium hydroxide in 20 mL of isopropanol. Under reflux, add drop wise of the isopropanol solution containing 5.7 g of the tetrazole obtained above. Continue stirring and reflux for 4h. Evaporate to dryness with the residue being extracted with chloroform. The extract was washed with l mol/L sodium hydroxide solution, dilute hydrochloric acid and water, dried by anhydrous sodium sulfate. Chloroform was distilled off with the residual liquid being subject to chromatograph on silica gel. Use chloroform-methanol (30: 1) for elution. Then apply methanol-water recrystallization to obtain 6.0 g of colorless needles cilostazol with the yield being 74% and the melting point being 158 ??~ 159 ℃.
Biological Activity
Potent phosphodiesterase III A (PDE3A) inhibitor (IC 50 = 0.2 μ M) and inhibitor of adenosine uptake. Has antimitogenic, antithrombotic, vasodilatory and cardiotonic properties in vivo . Also affects lipid levels in vivo .
Mechanism of action
Cilostazol exhibits greater selectivity than dipyridamole as an inhibitor of
PDE3A. The drug does not affect the other PDEs (PDEs 1, 2, or 4). Cilostazol
reversibly inhibit platelet aggregation induced by a number of stimuli, such as thrombin, ADP,
collagen, or stress from exercise. Additionally, cilostazol inhibits adenosine uptake,
leading to increased activity of adenosine at A1 and A2 receptors.
Clinical Use
Cilostazol, a quinolinone derivative, is a potent orally active antiplatelet drug approved for the
treatment of intermittent claudication (a peripheral artery disease resulting from blockage of blood
vessels in the limbs).
Drug interactions
Potentially hazardous interactions with other drugs
Anagrelide: avoid concomitant use. Antibacterials: concentration increased by
clarithromycin and erythromycin - consider
reducing cilostazol dose.
Antifungals: concentration possibly increased by
ketoconazole and itraconazole - consider reducing
cilostazol dose.
Antivirals: concentration possibly increased by
boceprevir, ritonavir and telaprevir - reduce
cilostazol dose to 50 mg twice daily.
Calcium-channel blockers: concentration increased
by diltiazem - consider reducing cilostazol dose.
Ulcer-healing drugs: concentration increased by
omeprazole - consider reducing cilostazol dose.
Metabolism
Cilostazol is rapidly absorbed after oral administration, particularly with a high-fat meal, which
greatly increases its bioavailability to approximately 90%. It is extensively metabolized in the liver by
various cytochromes. The most important cytochromes appear to be CYP3A4 and, to lesser extent,
by CYP2C19, with an elimination half-life of approximately 11 to 13 hours. Among the various
metabolites produced (11 metabolites are known), the two major metabolites are
3,4-dehydrocilostazol and 4′-trans-hydroxycliostazol. These two metabolites are
pharmacologically active. Studies indicate that the concomitant administration of cilostazol with
CYP3A inhibitors can greatly increase cilostazol blood concentrations, and a dose reduction may be
required. Similar results are seen when CYP2C19 is inhibited, leading to decreased formation
of 4-trans-hydroxycliostazol and significant increases in cilostazol and 3,4-dehydrocilostazol.
References
1) Schror (2002) The pharmacology of cilostazol; Diabetes Obes. Metab., 4 S14
Check Digit Verification of cas no
The CAS Registry Mumber 73963-72-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,3,9,6 and 3 respectively; the second part has 2 digits, 7 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 73963-72:
(7*7)+(6*3)+(5*9)+(4*6)+(3*3)+(2*7)+(1*2)=161
161 % 10 = 1
So 73963-72-1 is a valid CAS Registry Number.
InChI:InChI=1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)
73963-72-1Relevant articles and documents
METHODS FOR PREPARING CILOSTAZOL AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Paragraph 0101-0139; 0145, (2020/10/22)
The present invention relates to a method for preparing cilostazol and a pharmaceutical formulation comprising the same. A method for preparing crystalline A cilostazol and a cilostazol pharmaceutical preparation manufactured by using the same are provided. The cilostazol prepared according to the method of the present invention has high yield, has high purity, has a low impurity content, and has less side effects and excellent emission characteristics. A method for preparing cilostazol according to the present invention is characterized by having less environmental pollution compared to the conventional method using a single catalyst. (by machine translation)
Synthetic method of cilostazol
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Paragraph 0023; 0024; 0029; 0030; 0031; 0032; 0033-0040, (2017/12/27)
The invention discloses a synthetic method for cilostazol. In an alcohol-water system, inorganic alkali is taken as a catalyst, and quinolone derivatives and tetrazole derivatives react at the temperature of 75 to 80 DEG C to generate cilostazol. According to the invention, the alcohol-water mixed system is taken as a reaction medium, the reaction process is a homogeneous system, and the liquid expansion does not occur, and foam is not filled with a kettle. Furthermore, after the reaction is completed, a lower-layer alkaline containing water phase can be separated via standing still, and an upper-layer organic phase is cooled and crystallized to achieve the purification effect. The purity of the product can reach 99.6% or higher.
Convergent Three-Component Tetrazole Synthesis
Chandgude, Ajay L.,D?mling, Alexander
supporting information, p. 2383 - 2387 (2016/06/01)
A microwave-accelerated, simple, and efficient method for the construction of the 1,5-tetrazole scaffold was developed. It comprises a multicomponent reaction of an amine, a carboxylic acid derivative, and an azide source. On the basis of the availability of the archetypical starting materials, this method provided very versatile synthetic access to 1,5-disubstituted tetrazoles. The usefulness of this method was demonstrated in the synthesis of biologically important fused tetrazole scaffolds and the marketed drug cilostazol.